Nuclear hormone receptors are ligand induced transcription factors that regulate important biological functions, including cell growth and differentiation, development, metabolism, immune system, and oncogenesis. Ligand-independent pathways have also been reported and several nuclear receptors, called Orphan receptors, have no known ligand. One subfamily of orphan receptors with particular interest is the retinoid-related orphan receptors (RORs) subfamily. The crystal structures of RORalpha and beta have been solved complexed with ligands. However, no ligand has been yet identified for RORgamma. RORgamma seems to be critical for thymus development but little is known on its transcriptional activity. The discovery of ligands (natural or synthetic) for certain nuclear receptors has dramatically enhanced our understanding of the biological function of a particular receptor. More importantly, some of these ligands have shown promise in the clinic for the treatment of human diseases in which their receptors are involved. We hypothesize that i) based on the recently described ligands for RORalpha and beta, RORgamma transcriptional activity could also be modulated by selective compounds; ii) ligands for RORgamma (agonists and antagonists) can be rationally discovered through receptor modeling and virtual ligand screening of chemical libraries; iii) ligand identification will allow a better characterization of the physiological role of RORgamma discovery of its target genes, and deciphering of its mechanism of action. This is a highly innovative R21 proposal that will explore an important aspect of nuclear receptor research. The discovery of selective RORgamma ligands will have a significant impact on our knowledge of ROR biology and will open new avenues for future research: RORgamma activators can be used to identify receptor targets and deciphering of RORgamma biological function, which could translate into potential novel clinical applications in human diseases that can be related to RORgamma malfunction. [unreadable] [unreadable] [unreadable]